CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity

Martin K. Madsen, Anja Sofie Petersen, Dea S. Stenbæk, Inger Marie Sørensen, Harald Schiønning, Tobias Fjeld, Charlotte H. Nykjær, Sara Marie Ulv Larsen, Maria Grzywacz, Tobias Mathiesen, Ida L. Klausen, Oliver Overgaard-Hansen, Kristoffer Brendstrup-Brix, Kristian Linnet, Sys S. Johansen, Patrick M. Fisher, Rigmor H. Jensen, Gitte M. Knudsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


Objective: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). Background: CCH is an excruciating and difficult-to-treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited. Methods: In this small open-label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow-up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose. Results: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow-up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic–diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = −0.81), implicating this neural pathway in treatment response. Conclusion: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.

Original languageEnglish
Issue number1
Pages (from-to)55-67
Publication statusPublished - Jan 2024


  • cluster headache
  • functional connectivity
  • functional magnetic resonance imaging
  • hypothalamus
  • psilocin
  • psilocybin


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